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WO2005027832A2 - Compositions contenant de l'acide edta et utilisations de ces dernieres - Google Patents

Compositions contenant de l'acide edta et utilisations de ces dernieres Download PDF

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Publication number
WO2005027832A2
WO2005027832A2 PCT/US2004/029664 US2004029664W WO2005027832A2 WO 2005027832 A2 WO2005027832 A2 WO 2005027832A2 US 2004029664 W US2004029664 W US 2004029664W WO 2005027832 A2 WO2005027832 A2 WO 2005027832A2
Authority
WO
WIPO (PCT)
Prior art keywords
edta
patient
composition
atherosclerosis
therapeutic agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2004/029664
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English (en)
Other versions
WO2005027832A3 (fr
Inventor
Raymond C. Kurzweil
Terry Grossman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ray and Terry's Health Products Inc
Original Assignee
Ray and Terry's Health Products Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ray and Terry's Health Products Inc filed Critical Ray and Terry's Health Products Inc
Publication of WO2005027832A2 publication Critical patent/WO2005027832A2/fr
Publication of WO2005027832A3 publication Critical patent/WO2005027832A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • TECHNICAL FIELD This invention relates to EDTA containing compositions and therapeutic uses thereof.
  • Ethylenediamine tetra-acetic acid binds to metals, for example transition state metals, and is used therapeutically for the treatment of heavy metal accumulation.
  • EDTA Ethylenediamine tetra-acetic acid
  • Atherosclerosis is a process where cholesterol, calcium and other minerals accumulate on the inside lining of blood vessels and, over time, clog them. This process, which is often associated with aging, is often referred to as hardening of the arteries, atherosclerosis and arterial plaque buildup. Atherosclerosis contributes to and accounts for the high numbers of individuals suffering from cardiovascular disease in the United States and other developed countries.
  • EDTA can bind to metals deposited in the arterial wall and in plaques on the arterial walls of patients suffering from atherosclerosis.
  • Intravenous EDTA is administered by some "complementary" physicians on an outpatient basis to treat atherosclerosis.
  • the intravenous administration of EDTA is time consuming and expensive.
  • a preferable method of treatment is one where the patient can administer the treatment himself, e.g. orally. While oral EDTA is available, its effectiveness has been limited by its poor absorption bioavailability.
  • the composition also includes a pharmaceutical carrier or an additional therapeutic agent such as an ACE inhibitor, a calcium channel blocker, a beta-blocker, or a diuretic.
  • a pharmaceutical carrier or an additional therapeutic agent such as an ACE inhibitor, a calcium channel blocker, a beta-blocker, or a diuretic.
  • an orally available composition including piperine and EDTA is provided.
  • an orally available composition including enteric coated EDTA or a pharmaceutically acceptable derivative or pro-drug thereof is provided.
  • the enteric coating can include cellulose acetate phthalate or hydroxypropylmethylcelmlose phthalate.
  • the composition can also include a pharmaceutical carrier or an additional therapeutic agent such as an ACE inhibitor, a calcium channel blocker, a beta-blocker, or a diuretic, hi some instances, the additional therapeutic agent is a statin, hi some instances, the composition can also include piperine.
  • an orally available composition including enteric coated EDTA is provided.
  • the composition can also include piperine.
  • a method for the treatment or prevention of atherosclerosis is provided. The method includes identifying a patient having atherosclerosis or at risk of having atherosclerosis, and orally administering to the patient a composition including EDTA or a pharmaceutically acceptable prodrug or derivative thereof and piperine. In some instances the EDTA is enteric coated.
  • the method also includes administering to the patient an additional therapeutic agent such as an ACE inhibitor, a calcium channel blocker, a beta-blocker, or a diuretic.
  • the patient can be identified as having atherosclerosis or being at risk of having atherosclerosis using a calcium score (a measurement obtained by performing an ultrafast electron beam CT scan of the coronary arteries), hi some instances the method may also reduce the calcium score.
  • a method of the treatment or prevention of atherosclerosis includes identifying a patient having atherosclerosis or at risk for having atherosclerosis, and orally administering to the patient a composition including enteric coated EDTA or a pharmaceutically acceptable prodrug or derivative thereof.
  • the composition also includes piperine.
  • the method also includes administering to the patient an additional therapeutic agent such as an ACE inhibitor, a calcium channel blocker, a , beta-blocker, or a diuretic.
  • the patient can be identified as having atherosclerosis or being at risk of having atherosclerosis using a calcium score.
  • the method may reduce the calcium score of the patient.
  • Another aspect of the invention includes a method for the treatment of heavy metal accumulation. The method includes identifying a patient having heavy metal accumulation, and orally administering to the patient a composition comprising EDTA or a pharmaceutically acceptable prodrug or derivative thereof and piperine. The composition can be enteric coated. The composition can also be administered together with an additional therapeutic agent.
  • Another aspect of the invention includes a method of the treatment heavy metal accumulation, where the method includes identifying a patient having heavy metal accumulation, and orally administering to the patient a composition comprising enteric coated EDTA or a pharmaceutically acceptable prodrug or derivative thereof.
  • the composition also includes piperine.
  • the method also includes administering to the patient an additional therapeutic agent.
  • EDTA is of a time release formulation
  • a patient can take higher dosages, as each dose is released in a controlled manner into the blood stream.
  • DETAILED DESCRIPTION EDTA binds to metals in the body. Described below are techniques used in the use and preparation of orally available EDTA compositions in patients having atherosclerosis or heavy metal accumulation.
  • the invention also relates to compositions including EDTA related compounds such as cyclohexyl EDTA monoanhydride (CDTAMA) as described in U.S. Patent 5,021,571, or the EDTA related compounds described in U.S. Patent 6,080,785 both of which are incorporated by reference in their entirety.
  • CDTAMA cyclohexyl EDTA monoanhydride
  • the effectiveness of the composition can be determined, for example, using laboratory tests showing a decrease in amount of toxic heavy metals.
  • the effectiveness of the compound can be determined, for example, by the patient's improved performance on a stress test, decrease in chest pain, or decrease in a patient's shortness of breath.
  • a possible alternative to monitor the effectiveness of a therapeutic agent in treating coronary artery disease includes the use of coronary artery calcium as a marker for calcified plaque (calcified deposits of cholesterol and fat buildup) in a blood vessel. Plaque formation is also known as atherosclerosis.
  • Coronary artery calcium often occurs years or decades before the development of heart disease symptoms such as chest pain or shortness of breath.
  • Electron beam computerized tomography is a very sensitive method of detecting this calcium, and is therefore a good screening test for coronary atherosclerosis.
  • the calcium score for each artery reflects the total amount of calcium in that specific artery of the heart. The total calcium score is equal to the total amount of coronary artery calcium in the heart. Because coronary artery calcium reflects the total amount of calcified plaque in the heart, the higher the calcium scores, the greater the amount of atherosclerosis in the heart.
  • the calcium score does not correlate directly to the percentage narrowing of an artery, but it does correlate with the severity of the underlying coronary atherosclerosis (total plaque burden). However, the higher the calcium score in the heart, the greater the probability of a significant narrowing of arteries throughout the patient.
  • the calcium score is used to determine the calcium percentile, which compares the patient's calcium score to that of other asymptomatic or symptomatic people of the same age and sex.
  • the calcium score in combination with the calcium percentile, enables a physician to determine the risk to a patient of developing symptomatic coronary artery disease, and to measure the progression of disease and the effectiveness of treatment. Table 1 below provides an example of a correlation of calcium scores to risk of Coronary Artery Disease (CAD).
  • Table 1 Calcium Scores and correlation to CAD
  • enteric coating does not dissolve in the acidic environment of the stomach, but rather dissolves in the alkaline environment of the small intestine. Accordingly, the drug (e.g., EDTA or a related compound) is able to pass through the stomach and is released from the small intestine, which provides improved bioavailability.
  • Methods of enteric coating are known to those of skill in the art as seen for example in C. Signorino, "Aqueous Enteric Coating," Pharm. Technol. Tableting & Granulation Yearbook 25-26 (1999) and M.P. Jordan et al, "A Comparison of the Performance Characteristics of Enteric Film Coating Systems," AAPS National Meeting (October 1999).
  • EDTA is in a "time-release" formulation.
  • time-release formulation provides a more even amount of active drug (e.g., EDTA) in the blood stream over a prolonged period of time, thus reducing or in some instances avoiding the frequent peaks and valleys of medication levels one can encounter using more traditional methods of oral administration. Accordingly, the patient is provided with a more stable therapeutic environment.
  • active drug e.g., EDTA
  • Another advantage of the time release formulation is that it allows the patient to take dosages of the EDTA or EDTA related compound with less frequency than would be required with uncoated EDTA.
  • ACE inhibitor refers to an antihypertensive drug that blocks the formation of angiotensin in the kidney, leading to relaxation of the arteries and promotes the excretion of salt and water by inhibiting the activity of the angiotensin converting enzyme.
  • calcium channel blocker refers to a pharmaceutical agent that prevents or slows the influx of calcium ions into smooth muscle cells. Calcium channel blockers can be used, for example, to treat some forms of angina pectoris and some cardiac arrhythmias.
  • statin refers to of pharmaceutical agent that acts by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, an enzyme involved in the liver cholesterol synthesis.
  • HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl) 4 salts.
  • alkali metal e.g., sodium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., sodium
  • N-(alkyl) 4 salts e.g., sodium
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the compositions of this invention will be administered from about 1 to about 6 times per day.
  • EDTA or an EDTA related compound is administered together with piperine
  • the piperine is administered at about 0.2-5% (wt/wt) (e.g., 0.2-1.0, 1.0-2.5, or 2.5-5 % wt/wt) relative to the EDTA or related compound.
  • wt/wt a weight/weight ratio
  • % wt/wt a weight/weight ratio
  • Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
  • compositions of this invention can include EDTA or a pharmaceutically acceptable derivative or prodrug thereof; an additional agent including for example, piperine, acebutolol, bisoprololm, captopril, enalapril, hydrochlorothiazide, etc; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • compositions of this invention include EDTA or a pharmaceutically acceptable derivative or prodrug thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the compositions delineated herein include EDTA and derivatives thereof, as well as additional therapeutic agents if present, in amounts effective for achieving a modulation of disease or disease symptoms, including atherosclerosis or symptoms thereof.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • compositions of this invention include a combination of EDTA or a pharmaceutically acceptable prodrug or derivative thereof and one or more additional therapeutic or agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and e.g., between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose 'regimen, from the compounds of this invention.
  • those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • the compounds, compositions, and methods of combination therapy delineated herein are useful to treat atherosclerosis and related symptoms.
  • the concept of "treating” or “treatment” refers to activity that prevents, alleviates, or ameliorates any primary phenomena or secondary symptoms associated with atherosclerosis or heavy metal accumulation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne des compositions d'acide EDTA et des compositions liées à l'acide EDTA, et des procédés d'utilisation de ces dernières. Les compositions de l'invention présentent une biodisponibilité améliorée par rapport à l'acide EDTA seul. Les compositions précitées peuvent être utilisées pour traiter ou prévenir l'athérosclérose ou pour traiter l'accumulation des métaux lourds.
PCT/US2004/029664 2003-09-12 2004-09-13 Compositions contenant de l'acide edta et utilisations de ces dernieres Ceased WO2005027832A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US50282003P 2003-09-12 2003-09-12
US60/502,820 2003-09-12

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WO2005027832A2 true WO2005027832A2 (fr) 2005-03-31
WO2005027832A3 WO2005027832A3 (fr) 2005-06-16

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WO (1) WO2005027832A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117660A3 (fr) * 2005-05-04 2007-01-04 Clio Pharmaceutical Corp Methode de traitement du cancer et des maladies coronaire, inflammatoire et maculaire combinant la modulation de proteines dependantes du zinc et/ou du cuivre

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7563460B2 (en) * 2004-02-26 2009-07-21 Med Five, Inc. Enteric coated oral pharmaceutical to erode kidney stones
US20090202516A1 (en) 2008-02-08 2009-08-13 Prothera, Inc. Inhibition and treatment of gastrointestinal biofilms

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3838196A (en) * 1972-09-25 1974-09-24 J Mercer Method of treating arteriosclerosis
US5536506A (en) * 1995-02-24 1996-07-16 Sabinsa Corporation Use of piperine to increase the bioavailability of nutritional compounds
WO2000000186A1 (fr) * 1998-06-30 2000-01-06 American Medical Research, Inc. Procede de traitement des troubles topiques
WO2002064130A1 (fr) * 2001-02-15 2002-08-22 Pfizer Products Inc. Composes de recepteurs actives de la proliferation des peroxysomes (ppar)
AU2003233583A1 (en) * 2002-05-24 2003-12-12 Agennix Incorporated Oral lactoferrin in the treatment of respiratory disorders
GB0220182D0 (en) * 2002-08-30 2002-10-09 Cardiovascular Res Inst Maastr Organic compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117660A3 (fr) * 2005-05-04 2007-01-04 Clio Pharmaceutical Corp Methode de traitement du cancer et des maladies coronaire, inflammatoire et maculaire combinant la modulation de proteines dependantes du zinc et/ou du cuivre

Also Published As

Publication number Publication date
US20050112200A1 (en) 2005-05-26
WO2005027832A3 (fr) 2005-06-16
US8685374B2 (en) 2014-04-01

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